title: A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma: case report.
abstract: BACKGROUND
  The case presented here describes the clinical evolution of a pituitary carcinoma from an atypical prolactinoma after temozolomide (TMZ) treatment. The mechanism of acquisition of TMZ resistance was analyzed.
  
  
  METHODS
  A 60-year-old woman with atypical prolactinoma had been treated for 7 years with multiple therapies, including dopamine agonists, surgical intervention (5 times), conventional radiotherapy, and radiosurgery. The patient deteriorated as a result of tumor enlargement. Ten cycles of TMZ therapy, 200 mg/m for 5 days every 4 weeks, improved the patient's performance status and caused tumor shrinkage. Six months after discontinuation of TMZ, the tumor progressed into pituitary carcinoma with tumor regrowth and intraventricular dissemination. TMZ therapy was ineffective this time. A sixth surgery and salvage chemotherapy failed to improve the patient's condition, and she died 9 years after the first diagnosis. Throughout the treatment course, O6-methyl-guanine-DNA methyltransferase (MGMT) was immunonegative in the tumor specimens, including the TMZ-refractory pituitary carcinoma. Mutation of p53 was identified in both the atypical prolactinoma and pituitary carcinoma. In contrast, major differences were noted for mismatch repair protein MSH6 immunostaining: Although MSH6 was diffusely immunopositive in the atypical adenoma, it became immunonegative when the tumor evolved into TMZ-refractory pituitary carcinoma.
  
  
  CONCLUSIONS
  Loss of MSH6 occurred during the progression from an atypical prolactinoma to a pituitary carcinoma, which may have caused resistance to TMZ treatment. This case suggests that preserving MSH6 function is essential for responsiveness to TMZ treatment in MGMT-negative and p53-mutated atypical pituitary adenoma or pituitary carcinoma.
authors.affiliation: Department of Neurosurgery, Teikyo University Chiba Medical Center, Ichihara City, Chiba, Japan.
authors.forename: Mineko
authors.initials: M
authors.lastname: Murakami
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizutani
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Asano
authors.forename: Hideki
authors.initials: H
authors.lastname: Katakami
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ishida
authors.forename: Koji
authors.initials: K
authors.lastname: Takano
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okinaga
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuno
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015254:DNA Modification Methylases / Q000096:biosynthesis; D045643:DNA Repair Enzymes / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011388:Prolactin / Q000378:metabolism; D015175:Prolactinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D011388:Prolactin; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide